This is a competing renewal to study the structure and function of the prefrontal cortex in nonhuman primates. The proposed research has the long- range goal of understanding cognitive processes in the human brain through animal models. Its focus is on the principal sulcus (PS) (Walkers'area 46) of the macaque dorsolateral prefrontal cortex; this region of the primate cortex is essential for the process of working memory. Our specific goal in this grant is to provide a neurobiological foundation for understanding the memory functions of the PS at the areal, network, column and single cell levels. A series of anatomical studies will combine pathway tracing and electrophysiology and, in some instances immunocytochemistry, to examine selected visual, motor and intrinsic connections of prefrontal columns upon which memory functions are mapped. In complementary studies, a battery of functional approaches, e.g. intracortical injections of bicucculine for temporary disruption of function (Specific Aim #2), single- and double-label 2-deoxyglucose (Specific Aims #3 and #4) and finally single cell recording studies (Specific Aim #5) conducted in animals trained to perform memory-guided and sensory-guided oculomotor delayed response tasks are designed to provide a comprehensive analysis of the topography and dynamics of working memory in prefrontal cortex. These studies will also test the hypothesis that areas anatomically interconnected with the PS and parietal cortex are likewise dedicated to spatial cognition, each making a distinctive contribution within a distributed network defined by circuitry. The 2-deoxyglucose metabolic mapping technique allows visualization of metabolic activity in all areas of the brain during a given behavioral condition; and the double-label version of this method, developed in this laboratory, can address the long-standing issue of the cortical column as the functional unit of the cerebral cortex by examining the same cortical columns under two behavioral conditions in the very same animal. The columnar basis of working memory at the cellular level will be addressed by combined anatomical tracing and single cell recording studies. The proposed studies should advance our understanding of the circuit and cellular basis of cognitive functions and their breakdown in mental disease.